Age-Associated B Cells in Immunosenescence

The adaptive immune system consists of many different types of cell, undertaking many different tasks, all falling into the two broad categories of T cells and B cells. With age, the immune system falls into a chronic state of inflammation and overactivation (inflammaging) at the same time as it becomes ever less capable of defending tissues against pathogens and rogue cells (immunosenescence). Researchers have identified numerous potentially harmful subpopulations of both T and B cells in the aged immune system, and in the case of B cells have even selectively removed and replaced them, a procedure that resulted in improved immune function in mice.

That demonstration in mice was accomplished nearly a decade ago, and it is disappointing that comparatively little progress towards the clinical application of this sort of approach to immune aging has occurred since then. The evidence, from many animal studies and the few human trials of immune cell clearance undertaken, clearly shows that removing and replacing the immune system is beneficial because it destroys problem populations of immune cells. The challenge lies in producing a method of clearance that has few risks and side-effects, but the component parts of that technology certainly already exist - just look at Oisin Biotechnologies' target cell destruction platform for example.

Humoral immune responses mediated by B cells are important for adaptive immunity. B cells produce a diverse set of antibodies, which help in effectively eliminating antigens including pathogens. In addition, B cells play an indispensable role in the immune system via presentation of antigens and secretion of cytokines. In aged individuals, a spectrum of immune system alterations, termed "immune senescence," result in a blunted adaptive immune response, an increased tendency for inflammatory responses, enhanced susceptibility to infections, and an increased production of autoantibodies. Multiple factors may contribute to these immune activity changes. T cells have been shown to participate in immune senescence. However, the role of B cells in this respect remains unclear.

Recent findings illustrate conspicuous shifts in B cell subsets in the elderly, suggesting that age-related changes in B cells may contribute to immune senescence. The discovery of a subset of B cells that express T-bet, termed age-associated B cells (ABCs), has drawn significant attention in recent years. Initially isolated from aged donors and found to be closely associated with immune senescence, these cells were expected to provide a novel therapeutic avenue for autoimmune diseases.

These B cells first accumulated in the spleen and increased significantly in the bone marrow with age. ABC phenotypes are distinct from other B cell subsets. ABCs expressed similar levels of IgM and lower levels of IgD compared to follicular B cells. In addition, cell cycle analyses showed that ABCs were quiescent, suggesting that they are not a subset of self-renewing cells. Because ABCs were explored using mouse models, the existence of similar cells in aged humans may need confirmation. More interestingly, B cells with phenotypes similar to that of ABCs appear in both mice and humans, during the course of certain autoimmune diseases, and following some viral infections.

ABCs responded only to TLR7 and TLR9 stimuli in vitro. They were found to secrete antibodies upon TLR stimulation rather than upon BCR stimulation. Since TLRs are commonly associated with skewing toward inflammatory responses, increased numbers of ABCs may yield more innate immune responses, characterized by low-affinity antibody, and inflammatory processes. Furthermore, ABCs directly participate in producing autoantibodies, indicating that they are associated with serious autoimmunity seen in the aged. Considered together, ABCs appear to play multiple roles in age-associated alteration of immune activity. However, antigen-presentation ability is mainly displayed in in vitro assays. Interaction of ABCs with the other immune cells in vivo may need further exploration.



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